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We read with great interest the article by Chiari et al.1 regarding a potential role of endothelial nitric oxide synthase in isoflurane-induced delayed preconditioning in rabbit myocardium. The authors are to be congratulated for performing an important study about the remote effects of isoflurane in attenuating myocardial infarct after acute coronary occlusion and reperfusion. In particular, they addressed the potential role of endothelial nitric oxide synthase and subsequently of nitric oxide in isoflurane-induced myocardial protection.

Nitric oxide donors have been shown to mimic the protective effects of delayed ischemic preconditioning in rabbits.2 The protective effect of nitric oxide donor was completely abrogated when this agent was given in conjunction with the peroxynitrite (ONOO-) and hydroxyl radical (.OH) scavenger mercaptopropionyl glycine,2 suggesting nitric oxide induced late preconditioning involved the generation of reactive oxygen species. This is similar in nature to isoflurane in that isoflurane preconditioning requires the generation of reactive oxygen species as a trigger.3 Furthermore, transient systemic ischemic preconditioning enhanced early functional recovery of reperfused hearts in the rabbits, accompanied by an increase in plasma nitric oxide concentration as well as increases in plasma superoxide dismutase activity.4 This latter observation seems to suggest nitric oxide as a potential mediator of ischemic preconditioning in rabbits. This is supportive of the study of Chiari et al.1 showing that endogenous nitric oxide may function as a mediator of isoflurane-induced delayed preconditioning.

It should be noted, however, that in all of the studies1–4 mentioned above, the duration of coronary occlusion was limited to 30 min. A study conducted by Kehl et al.5 (from the same research group as Chiari et al.1) clearly demonstrated that isoflurane did not produce a delayed preconditioning against myocardial infarction in vivo
in dogs when the duration of coronary occlusion was extended to 60 min. Although the animal species used are different in the two studies,1,5 the duration of coronary occlusion could have played a determinant role regarding the effectiveness of isoflurane in inducing delayed preconditioning against myocardial infarct. It is unexpected that Chiari et al.1 did not comment on this potential limitation of isoflurane preconditioning effects. Study has shown that in ischemic-reperfused isolated guinea pig hearts, the therapeutic time frame for anesthetic preconditioning against postischemic contractile dysfunction and infarction is approximately 25–40 min.6 The protection is maximal when ischemic duration is between 30 and 35 min. This suggests that anesthetic preconditioning may be useful therapy only if the typical duration of ischemia during coronary artery bypass falls within this range. Therefore, we have good reason to postulate that isoflurane-induced delayed preconditioning, if any, is confined to a specific time frame.

As commented by Chiari et al.
in the Discussion, aging modulates (reduces the efficiency of) anesthetic preconditioning. One possible explanation for this phenomenon is that antioxidant capacity is reduced with aging. That is, aging is associated with increased formation of reactive oxygen species. Therefore, theoretically, further enhancement of oxygen free radical production by volatile anesthetics may even prove to be detrimental to an aged population. The oxygen free radical–induced lipid peroxidation end product 15-F2t-isoprostane per se
has been shown to be an independent risk marker of cardiac complications and can exacerbate myocardial ischemia–reperfusion injury.7 In contrast to volatile anesthetics, the intravenous anesthetic propofol has antioxidant property and has been shown experimentally to better protect hearts of aging animals than hearts of younger animals against postischemic myocardial injury.8 Large prospective clinical trials comparing volatile anesthetic preconditioning and intravenous “anesthetic treatment” or trials comparing a combination of the two are merited, in particular, in the aged population or in those patients with an expected duration of ischemia during coronary artery bypass longer than 40 min.

*Renmin Hospital, Wuhan University, Wuhan, China, and University of British Columbia, Vancouver, British Columbia, Canada.